Dopaminergic network differences in human impulsivity

Abstract

Dopamine (DA) has long been implicated in impulsivity, but the precise mechanisms linking human variability in DA signaling to differences in impulsive traits remain largely unknown. By using a dual-scan positron emission tomography approach in healthy human volunteers with amphetamine and the D2/D3 ligand [18F]fallypride, we found that higher levels of trait impulsivity were predicted by diminished midbrain D2/D3 autoreceptor binding and greater amphetamine-induced DA release in the striatum, which was in turn associated with stimulant craving. Path analysis confirmed that the impact of decreased midbrain D2/D3 autoreceptor availability on trait impulsivity is mediated in part through its effect on stimulated striatal DA release.

Fig. 1

(A) Rendering of two separate SPMs depicting negative correlations between BIS-11 scores and D2/D3 binding and positive correlations between BIS-11 scores and amphetamine-induced DA release (corrected for multiple comparisons at the cluster-level, p_corrected < 0.05; clusters defined using a height threshold of t > 3). For the D2/D3 binding, inverse associations emerged in the DA midbrain [anteriorly in the VTA, centered at 6, −3, −11 (x, y, z; MNI space) and posteriorly in the retrorubral fields)] as well as more anteriorly in the mammillary bodies and hypothalamus (not shown). Peak coordinates for the striatal AMPH-induced DA release correlations = −16, 15, 5 (left) and 20, 23, −3 (right); cluster sizes = 167 voxels (left) and 216 voxels (right). Colorbar represents Fisher-transformed z-statistic values for the correlations (d.f. = 31). SPMs rendered on a T1-weighted MRI template brain, with cuts at z = −11 and y = 16. (B) Path analysis demonstrating that the influence of midbrain D2/D3 availability on trait impulsivity is mediated through an impact on striatal amphetamine-induced DA release. Path “A” shows path coefficients for the effect of midbrain D2/D3 binding (cluster highlighted with red circle) on striatal DA release (left/right striatum). Path “B” shows the path coefficient for the effect of striatal DA release on trait impulsivity (left/right striatum). Paths “C” and “C’” show coefficients for the total (dashed line) and direct (solid line) effects of midbrain D2/D3 binding on trait impulsivity. All coefficients standardized. Sobel test for mediation: Z = −1.94, p = 0.05, with left and right striatum modeled simultaneously.